There are many circumstances in which it is desirable to measure the concentration of an analyte in blood. One of the most important is the measurement of blood glucose concentration, of crucial importance to the management of diabetes. It is estimated by Danaei et al. (“National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants”, Lancet, 2011, 378(9785):31-40) that 370 million people in the world suffer from diabetes and the WHO predicts that diabetes will be the 7th leading cause of death in 2030 (“Global status report on non-communicable diseases 2010”, WHO 2011). At present, the only accurate and inexpensive way for diabetics to measure their blood glucose concentration is by taking a blood sample, usually by pricking a finger, and placing a drop of blood on a test strip. A measurement of the change of colour of the strip or a measurement of a redox reaction on the strip after application of the blood sample provides an indication of the blood glucose concentration.
Inexpensive automated equipment exists to estimate the change in colour or the electrochemical reaction but there is no consumer equipment capable of making the measurement without taking a blood sample and many diabetics have to do this several times per day.
Other analytes such as alcohol, haemoglobin, creatinine, cholesterol, stimulants or other drugs, including illegal or otherwise forbidden substances, are also important and again there is no accurate, reliable and inexpensive way of estimating their concentration non-invasively.
In principle, absorption spectroscopy would be a good method for estimating the concentration of an analyte but this is difficult in vivo if the contribution to the absorption from the analyte is small compared to the absorption by other materials in the blood and tissue, especially if the analyte has few or no narrow absorption bands in the useable near infra-red (NIR) and/or if those bands are overlapping with those of water, which is the predominant component of blood and tissue. For example, Klonoff (“Non-invasive blood glucose monitoring”, Diabetes Care, 20, 3, 435-437 1997) states: “Glucose is responsible for <0.1% of NIR absorbed by the body. Water, fat, skin, muscle and bone account for the vast majority of NIR absorption. Perturbations in the amounts of these substances can alter NIR absorption and thus invalidate the calibration formula for correlating light absorption with blood glucose concentrations . . . ”.
Even if this could be overcome, the measurement of the specific absorption would require a precise spectrometer that is not easily made inexpensively and reliably.
U.S. Pat. No. 4,882,492 in 1989 disclosed an invention employing “non-dispersive correlation infra-red spectroscopy”. According to this disclosure, broad spectrum NIR light is transmitted through or scattered by a body part. The emergent light is split into two beams. One beam passes through a filter consisting of a solution of the analyte and the other through a neutral density filter. The analyte filter absorbs from the first beam substantially all of the light in the spectral absorption bands of the analyte. The neutral density filter reduces the power of the second beam to be similar to the power of the first beam. Any difference between the powers of the light in the two beams arises solely from the amount of light absorbed by the analyte in the body part.
The US patent alleges that spectral specificity is achieved without the need for a dispersive element (a spectrometer) but this depends crucially on the balance between the two beams and the exact characteristics of the neutral density filter. It also does not distinguish analyte in the blood from analyte in the surface layers of the tissue. In practice, this is likely to prevent the device ever being reliable or accurate.
Fine (Chapter 9 of Handbook of optical sensing of glucose in biological fluids and tissues, 2009) describes a technique for estimating glucose concentration by the change in the optical scattering of aggregated red blood cells. It uses an analogy with a pulse oximeter and correlates the scattered signal with the variation of area of the artery as the heart beats, thus making the signal preferentially sensitive to the glucose in the arterial blood. However, Fine concludes that this technique is ineffective, in part because the change in arterial area is relatively small.
WO 2013/001265 discloses significant improvements on U.S. Pat. No. 4,882,492. Claim 25 of WO 2013/001265 relates a personal hand-held monitor (PHHM) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, the signal acquisition device being integrated with a personal hand-held computing device (PHHCD), wherein the signal acquisition device comprises a blood photosensor having a photo-emitter for transmitting light to a body part of a user, a photo-detector for detecting light transmitted through or scattered by the body part and an optical cell, containing an analyte to be detected, through which light transmitted through or scattered by the body part passes before it reaches the photo-detector, wherein the processor of the PHHM is adapted to process signals obtained from the photo-detector in the presence of the body part and in the absence of the body part to provide a measurement of the concentration of the analyte in the user's blood. WO 2013/001265 also discloses using the principle of two beams, one of which passes through a cell containing the analyte and compares the power in each beam.
FIGS. 1 and 2 in the attached drawings, which are identical to FIGS. 9 and 11 of WO 2013/001265, show two arrangements of blood photosensors to be used in the PHHM claimed in claim 25 of WO 2013/001265, which may be incorporated into a PHHCD, or may be connected to a PHHCD or may be constructed as a stand-alone device with its own user interface, power supply and other electronic and mechanical components.
As shown in FIG. 1, a photo-emitter (81) transmits a beam of light that passes through a filter (82) to select the spectral band of the light to be used. The spectral band is chosen to allow inexpensive components and materials to be used whilst maximising the sensitivity and discrimination with respect to the analyte. The beam is collimated by a lens (83) to shine through a body part, such as a finger (84). A beam splitter (85) divides the beam between a non-analyte cell (86) and analyte cell (87). Photo-detectors (88) measure the intensity of the beam after it has passed through each cell. A differential amplifier may be used to amplify the difference in signals from the two photo-detectors.
FIG. 2 shows another arrangement in which the photo-emitter and photo-detector are on the same side of a body part, the photo-detector being sensitive to the light scattered back from the body part. A moving mirror (101) reflects light sequentially to each of two fixed mirrors (102) and hence to the non-analyte cell (86) or analyte cell. The photo-detector (108) measures the intensity of the beam that has passed the cells.
In each of these arrangements, the difference between the intensity when the beam of light has passed through the non-analyte cell and through the analyte cell is a measure of the amount of absorption by the analyte within the body part.
The invention disclosed in WO 2013/001265 goes some way towards the goal of a sensor that is non-invasive, inexpensive, accurate and reliable. However, it is not specific to the analyte contained in blood because the signal is also affected by analyte in the surrounding tissue. Further improvements are also desirable to reduce the cost of implementation and to improve accuracy.